Alcohol ingestion has long been associated with a predisposition to infection, dating back to early observations about tuberculosis. While alcohol's profound effects on cell-mediated immune mechanisms are well known, little information exists on the effects of alcohol intoxication on the predisposition to the Acquired Immunodeficiency Syndrome (AIDS) or in any of the opportunistic infections that characterize this eventually fatal condition. Currently, systemic infections due to the Mycobacterium avium complex are present in more than 50% of patients with the advanced clinical stages of AIDS but the role of alcohol in predisposing normal and immunosuppressed patients to mycobacterial infection is unknown. This research proposes to examine the specific mechanisms by which cellular immunity is compromised by ethanol so that dissemination of M. avium disease can occur. Mycobacterial are intracellular pathogens and there is mounting evidence that effective killing of bacilli within mononuclear phagocytes requires activation by a variety of recently described cytokines including tumor necrosis factor and colony stimulating factor; gamma interferon and interleukin-2 have no defined role. We have in vitro studies demonstrating that moderate degrees of alcohol exposure cause defects in the mononuclear cell killing of M. avium organisms and reduced bacterial clearance from blood of mice. We plan to investigate the effect of alcohol on (1) oxidative and nonoxidative bactericidal mechanisms of macrophages and Kupffer cells, (2) elaboration of cytokines (immunomodulator) and ethanol's effect on the activity of exogenous cytokines, (3) natural killer cell activity, (4) intramonocytic arachidonic acid pathways, (5) the ability of exogenous recombinant immunomodulators and prostaglandin inhibitors to reverse the mononuclear cell killing defect associated with alcohol. To test the effects of ethanol in an animal model we will determine if chronic exposure facilitates infection by M. avium, worsens outcome, and has an adverse effect on chemotherapy in beige mice, which have an AIDS-like immunodeficiency. This research seeks to identify the specific mechanisms by which alcohol induced injury can lead to infectious complications, such as caused by M. avium, and identify possible new therapeutic and prophylactic approaches.